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Trial registered on ANZCTR


Registration number
ACTRN12624001055594
Ethics application status
Approved
Date submitted
24/07/2024
Date registered
30/08/2024
Date last updated
15/09/2024
Date data sharing statement initially provided
30/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
The Paracetamol and Ibuprofen in Kids Intervention (PIKI) Trial
Scientific title
Randomised controlled trial of paracetamol versus ibuprofen for fever and pain in children under 2 years of age
Secondary ID [1] 312573 0
UoA 3729441
Secondary ID [2] 312578 0
AMRF 1123009
Universal Trial Number (UTN)
Trial acronym
PIKI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Febrile discomfort 334497 0
Paediatric fever 334498 0
Medication safety 334499 0
Medication efficacy 334500 0
Condition category
Condition code
Emergency medicine 331115 331115 0 0
Other emergency care
Anaesthesiology 331116 331116 0 0
Pain management
Infection 331118 331118 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ibuprofen oral suspension + paracetamol placebo.

Dose:
ibuprofen 10mg/kg (if greater than 3 months of age) oral liquid + paracetamol placebo oral liquid
ibuprofen 5mg/kg (if less than 3 months of age) oral liquid + paracetamol placebo oral liquid

Paracetamol placebo composition:
Sucralose NF
Xanthan Gum NF
Glycerin USP
Sorbitol USP
Microcrystalline Cellulose NF
Citric Acid USP
Sodium Citrate USP
Methyl Hydroxybenzoate (Methylparaben) NF
Propyl Hydroxybenzoate (Propylparaben) NF
Natural Orange Emulsion
Purified Water USP


As required for febrile discomfort, evidenced by a temperature of equal to or greater than 38° degrees Celsius and an EVENDOL score of greater than or equal to 4. To be administered by a health professional within the Emergency Department.

This study medicine will be administered once only, UNLESS the patient vomits within 10 minutes of the medicine being administered, in which case a repeat dose will be given.

Adherence to this intervention will be assessed by either research staff administering the study medicine themselves or direct observation of clinical staff administering the study medicine, and review of the patient's ED medication chart,

Allocation to intervention vs control group will be randomised and double-blinded.
Intervention code [1] 329096 0
Treatment: Drugs
Comparator / control treatment
Paracetamol + ibuprofen placebo.

Dose:
paracetamol 15mg/kg oral liquid + ibuprofen placebo oral liquid

Ibuprofen placebo composition:
Sucralose NF
Xanthan Gum NF
Glycerin USP
Sorbitol USP
Microcrystalline Cellulose NF
Citric Acid USP
Sodium Citrate USP
Methyl Hydroxybenzoate (Methylparaben) NF
Propyl Hydroxybenzoate (Propylparaben) NF
Water Soluble Orange Flavour
Purified Water USP


As required for febrile discomfort, evidenced by a temperature of equal to or greater than 38° degrees Celsius and an EVENDOL score of greater than or equal to 4. To be administered by a health professional within the Emergency Department.

This study medicine will be administered once only, UNLESS the patient vomits within 10 minutes of the medicine being administered, in which case a repeat dose will be given.

Adherence to this intervention will be assessed by either research staff administering the study medicine themselves or direct observation of clinical staff administering the study medicine, and review of the patient's ED medication chart,

Allocation to intervention vs control group will be randomised and double-blinded.
Control group
Active

Outcomes
Primary outcome [1] 338898 0
Change in severity of febrile discomfort
Timepoint [1] 338898 0
At 1.5 hours after study medicine administration
Secondary outcome [1] 437833 0
Change in severity of febrile discomfort (categorical)
Timepoint [1] 437833 0
At 1.5 hours and 4 hours after study medicine administration
Secondary outcome [2] 437835 0
Change in severity of febrile discomfort (continuous)
Timepoint [2] 437835 0
At 1.5 hours and 4 hours after study medicine administration
Secondary outcome [3] 437836 0
Change of temperature (categorical)
Timepoint [3] 437836 0
At 1.5 hours and 4 hours after study medicine administration
Secondary outcome [4] 437841 0
Change of temperature (continuous)
Timepoint [4] 437841 0
At 1.5 hours and 4 hours after study medicine administration
Secondary outcome [5] 437843 0
Total fluid intake
Timepoint [5] 437843 0
At 4 hours after study medicine administration
Secondary outcome [6] 437844 0
Parent/guardian satisfaction
Timepoint [6] 437844 0
At 4 hours after study medicine administration
Secondary outcome [7] 437845 0
Alternate antipyretic/analgesic for ongoing discomfort
Timepoint [7] 437845 0
Within 4 hours of the study medicine administration
Secondary outcome [8] 437846 0
Emergency Department (ED) length of stay
Timepoint [8] 437846 0
Obtained during retrospective medical record review, 28 days after ED presentation
Secondary outcome [9] 437849 0
Hospital length of stay (if admitted)
Timepoint [9] 437849 0
Obtained during retrospective medical record review, 28 days after ED presentation
Secondary outcome [10] 437851 0
Adverse events
Timepoint [10] 437851 0
Obtained during retrospective medical record review, 28 days after ED presentation
Secondary outcome [11] 437852 0
Serious adverse events
Timepoint [11] 437852 0
Obtained during retrospective medical record review, 28 days after ED presentation

Eligibility
Key inclusion criteria
1. Presenting to either Kidz First (Middlemore) ED, Starship Children's Hospital ED, Waitakere Hospital ED, Tauranga Hospital ED, or Christchurch Hospital ED
2. Aged 2 to 23 months old (chronological age)
3. Temperature of equal to or greater than 38.0 degrees Celsius (rectal/axillary/tympanic)
4. Moderate or severe discomfort/pain, defined as an EVENDOL score equal to or greater than 4.
Minimum age
2 Months
Maximum age
23 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants will not be enrolled if ANY of the following apply:
1. Administration of paracetamol less than 4 h or ibuprofen less than 6 h prior to trial screening (usual dosing interval)
2. Already received maximum 24 h dose of paracetamol (75 mg/kg per day) or ibuprofen (age <3 months: 20 mg/kg per day; age 3-23 months: 40 mg/kg per day ) in the preceding 24 h
3. Known paracetamol or ibuprofen hypersensitivity
4. Requiring immediate treatment for possible sepsis
5. Clinically unstable as determined by treating clinician
6. Active gastrointestinal bleeding or ulcers
7. Chronic renal failure
8. Chronic liver failure
9. Chronic cardiac failure
10. Known coagulopathy
11. Gross global developmental delay
12. Malignancy
13. Parent/guardian not available
14. Previous enrolment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Treatment group allocation will be concealed using sequentially numbered, opaque trial packs containing the trial medications.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using a computer-generated sequence with a variable block size per site to maintain allocation concealment, generated by the trial statistician, independent of trial investigators. Allocation concealment will be by a secure database, which contains the randomisation sequence accessible only to the trial statistician and independent data manager.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary outcome variable is the proportion of participants with relief of discomfort at 1.5 h. Prior studies comparing the analgesic efficacy of paracetamol vs. ibuprofen in similar aged cohorts to the proposed trial, but at later timepoints (24 to 72 h), have found effect sizes in the paracetamol group ranging from 38% to 90%. Prior studies comparing the analgesic efficacy of paracetamol vs. ibuprofen at similar timepoints to the proposed trial, but with older aged cohorts (4 to 17 years old), have found effect sizes in the paracetamol group ranging from 23% to 39%. We have used a conservative effect size in the paracetamol group of 50%, and aim to show an absolute difference between the two groups of =10%. Thus, with 90% power and a two-sided alpha of 0.05, we estimate that 516 participants in each group would detect an improvement (increase) in the primary outcome of =10% (or decrease of =10%) in the ibuprofen group anywhere in the published range (23% to 90%) of relief of discomfort for paracetamol. Assuming 5% attrition, a total of 1,086 participants (543 in each arm) will be recruited.

Recent ED census data support the feasibility of our recruitment target of 1,086 participants over 2 winters. In the preceding 12 months, the 6 EDs collectively saw 138,610 paediatric presentations, including 25,669 children aged 2 to 23 months in winter 2023. Twenty percent of paediatric ED visits in children aged 2 to 23 months are associated with fever (Kidz First data) (5,134). Thus, our sample size of 1,086 represents a recruitment target of 1 in 9 febrile children aged 2 to 23 months presenting to the 6 EDs over the 2 winters of proposed recruitment. Our previous ED studies have easily achieved this target.

Analysis will be by intention-to-treat by a biostatistician blinded to allocation. The primary outcome analysis will be a superiority comparison of the proportion of participants with relief of discomfort at 1.5 h, defined as EVENDOL score <4 (mild/no pain), using logistic regression including a stratification variable for site.

A per-protocol analysis of primary and secondary outcomes will be undertaken as a sensitivity analysis.

We plan to conduct subgroup analyses of the primary outcome by age (<6 vs. =6 months), ethnicity (Maori vs. non-Maori), and indication (bacterial illness (provision of antibiotics) vs. not). The indication analysis will be based on final diagnosis, and be exploratory in nature. Of note, stratification and identification of cause of febrile illness is not available at triage when patients usually present with undifferentiated fever.

Although all estimates will be given as 95% CIs, with a nominal two-sided type I error rate of 5%; we will not adjust secondary analyses for multiple analyses; secondary analyses will be considered exploratory.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2024
Actual
Date of last participant enrolment
Anticipated
31/08/2026
Actual
Date of last data collection
Anticipated
30/09/2026
Actual
Sample size
Target
1086
Accrual to date
Final
Recruitment outside Australia
Country [1] 26443 0
New Zealand
State/province [1] 26443 0

Funding & Sponsors
Funding source category [1] 317005 0
Charities/Societies/Foundations
Name [1] 317005 0
Auckland Medical Research Foundation
Country [1] 317005 0
New Zealand
Funding source category [2] 317010 0
Hospital
Name [2] 317010 0
Tupu Research Fund
Country [2] 317010 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Country
New Zealand
Secondary sponsor category [1] 319249 0
Government body
Name [1] 319249 0
Te Whatu Ora
Address [1] 319249 0
Country [1] 319249 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315763 0
Northern B Health and Disability Ethics Committee 
Ethics committee address [1] 315763 0
Ethics committee country [1] 315763 0
New Zealand
Date submitted for ethics approval [1] 315763 0
18/06/2024
Approval date [1] 315763 0
12/08/2024
Ethics approval number [1] 315763 0
2024 FULL 20591

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135714 0
Dr Eunicia Tan
Address 135714 0
Middlemore Hospital Emergency Department, 100 Hospital Road, Otahuhu, Auckland 2025
Country 135714 0
New Zealand
Phone 135714 0
+64 21 487771
Fax 135714 0
Email 135714 0
eunicia.tan@middlemore.co.nz
Contact person for public queries
Name 135715 0
Georgia Doyle
Address 135715 0
Middlemore Hospital Emergency Department, 100 Hospital Road, Otahuhu, Auckland 2025
Country 135715 0
New Zealand
Phone 135715 0
+64 21 0407709
Fax 135715 0
Email 135715 0
georgia.doyle@middlemore.co.nz
Contact person for scientific queries
Name 135716 0
Eunicia Tan
Address 135716 0
Middlemore Hospital Emergency Department, 100 Hospital Road, Otahuhu, Auckland 2025
Country 135716 0
New Zealand
Phone 135716 0
+64 21 487771
Fax 135716 0
Email 135716 0
eunicia.tan@middlemore.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The PIKI study uses identifiable individual patient data that are subject to restriction, including ethics, consent, and privacy issues. Anonymised data will be available on request from the corresponding author, where possible within these constraints for use.
When will data be available (start and end dates)?
From time of publication of main manuscript for 5 years.
Available to whom?
Researchers.
Available for what types of analyses?
Available for meta-analysis
How or where can data be obtained?
Anonymised data will be available on request from the Primary Investigator, Dr Eunicia Tan. She can be contacted at eunicia.tan@middlemore.co.nz


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.